5-41142845-G-A

Position:

• chr5-41142845-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000065.5(C6):​c.2785C>T​(p.Pro929Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: C6 NM_000065.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.159

Genes affected

C6 (HGNC:1339): (complement C6) This gene encodes a component of the complement cascade. The encoded protein is part of the membrane attack complex that can be incorporated into the cell membrane and cause cell lysis. Mutations in this gene are associated with complement component-6 deficiency. Transcript variants encoding the same protein have been described.[provided by RefSeq, Nov 2012]

C6 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03288406).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C6	NM_000065.5	c.2785C>T	p.Pro929Ser	missense_variant	18/18	ENST00000337836.10	NP_000056.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C6	ENST00000337836.10	c.2785C>T	p.Pro929Ser	missense_variant	18/18	1	NM_000065.5	ENSP00000338861.5
C6	ENST00000263413.7	c.2785C>T	p.Pro929Ser	missense_variant	18/18	1		ENSP00000263413.3
C6	ENST00000706654.1	n.952C>T		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 14, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with C6-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with serine at codon 929 of the C6 protein (p.Pro929Ser). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	10
DANN	Benign	0.84
DEOGEN2	Benign	0.031	T;T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.48	.;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.033	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.41	N;N
REVEL	Benign	0.027
Sift	Benign	0.56	T;T
Sift4G	Benign	0.55	T;T
Polyphen		0.0040	B;B
Vest4		0.055
MutPred		0.33		Gain of MoRF binding (P = 0.0294);Gain of MoRF binding (P = 0.0294);
MVP		0.41
MPC		0.035
ClinPred		0.074	T
GERP RS		0.76
Varity_R		0.078
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-41142947; COSMIC: COSV99667601;